ETV2/ER71 regulates hematovascular lineage generation and vascularization through an H3K9 demethylase, KDM4A

ETV2/ER71, an ETS (E-twenty six) transcription factor, is critical for hematopoiesis and vascular development. However, research about the molecular mechanisms behind ETV2-mediated gene transcription is limited. Herein, we demonstrate that ETV2 and KDM4A, an H3K9 demethylase, regulate hematopoietic and endothelial genes. Etv2 ^-/- mouse embryonic stem cells (mESCs), which fail to generate hematopoietic and endothelial cells, exhibit enhanced H3K9me3 levels in hematopoietic and endothelial genes. ETV2 interacts with KDM4A, and the ETV2-mediated transcriptional activation of hematopoietic and endothelial genes depends on KDM4A histone demethylase activity. The ETV2 and KDM4A complex binds to the transcription regulatory regions of genes directly regulated by ETV2. Mice lacking Kdm4a and Etv2 in endothelial cells (Cdh5Cre:Kdm:Etv2 ^f/f mice) display a more severe perfusion recovery and neovascularization defect, compared with Cdh5Cre:Kdm4a ^f/f mice, Cdh5Cre:Etv2 ^f/f mice, and controls. Collectively, we demonstrate that ETV2 interacts with KDM4A, and that this interaction is critical for hematovascular lineage generation and vascular regeneration.